Phosphate depletion is commonly seen in certain patient populations including alcoholics, malnourished, acutely ill patients, patients receiving parenteral nutrition, patients being re-fed after prolonged fasting, or dialysis patients. Oral repletion of phosphate may not be feasible if the patient is not able to eat, suffers from malabsorption or has continuing losses of phosphate that cannot be adequately treated by the oral route. In such clinical situations phosphate is commonly administered intravenously. This invention provides a method and pharmaceutical composition for administering pyrophosphate for the prevention or treatment of phosphate or pyrophosphate depletion.
Specifically, in patients with kidney failure, excess removal of phosphate and pyrophosphate anions can occur during hemodialysis or peritoneal dialysis. Depletion of these anions from tissues and plasma leads to disorders of bone and mineral metabolism including osteomalacia and calcification of soft tissues and bone disease.
Kidneys are integral to maintenance of normal bone and mineral metabolism including excretion of phosphate. Patients with kidney failure are unable to appropriately regulate serum mineral balance and tend to retain phosphate that is absorbed from the various dietary components. A high serum level of phosphate is associated with excessive secretion of parathyroid hormone and a tendency to calcification of the soft tissues including the blood vessels.
In dialysis patients, hyperphosphatemia is controlled by removal of phosphate during hemodialysis or peritoneal dialysis. Peritoneal dialysis is a continuous process during which a transfer of phosphates from the blood compartment to the peritoneal fluid occurs relatively efficiently. However, the usual three times a week hemodialysis is not able to remove all the phosphates absorbed and generated during the inter-dialytic interval. Therefore, the majority of patients on the usual three times a week hemodialysis are prescribed agents such as calcium acetate that bind dietary phosphate in the gut, thereby decreasing the absorption of dietary phosphate. It has been shown that increasing the efficiency of dialysis can improve general well-being and overall health of the patient, while preventing complications of kidney failure.
Conventional Hemodialysis (CHD), delivered thrice weekly, results in large biochemical and body fluid volume fluctuations with potentially hazardous peaks and troughs, is still highly unphysiologic. More frequent dialysis schedules may better mimic the normal physiological situation. These include short daily home hemodialysis (SDHD) and slow long-hours nocturnal hemodialysis (NHD) performed 6-10 hours nightly 6-7 times per week. The considerable clinical improvements when patients change to SDHD and NHD dialysis have been almost uniformly observed, and include better well-being and energy, better nutritional indices, higher hemoglobin, better blood-pressure control, much improved intra-dialysis tolerance with fewer cramps, hypotension, nausea, headaches, lesser post dialysis symptoms including fatigue, cramps and lightheadedness. The minor effect of short daily dialysis on phosphate removal-in contrast to the major effect of daily nocturnal dialysis, with its long, 8 hour sessions-probably is related to the complex phosphate kinetics during and after dialysis. After the start of a dialysis session, serum phosphate decreases rapidly to low, though further constant, serum concentrations, only to rise at the end of a 4-hour session. This rapid decrease is caused by an effective phosphate clearance through the dialyzer in the beginning. Thereafter, phosphate starts to be transferred to the blood from extravascular compartment, possibly bone, during the course of a dialysis session, probably due to an active mechanism, triggered by the fall in serum phosphate. This inter-compartmental transfer of phosphate prevents a further decrease in serum phosphate. However, it also determines the rate of phosphate removal during the course of a dialysis session, independent from the type of dialyzer or PTH level. This inter-compartmental transfer can lead to tissue depletion of phosphate.
However, large amounts of phosphate, matching daily intake, can only be removed through long sessions, as in the case of nocturnal hemodialysis. The creation of more “starting periods” with high initial removal rates through frequent dialysis sessions appear to be less effective. The mass balance studies by Al-Hejaili et al. have showed that phosphate removal by NHD (43.5±20.7 mmol) was significantly (P<0.05) higher than by SDHD (24.2±13.9 mmol) but not by CHD (34.0±8.7 mmol) on a per-treatment basis (Al-Hejaili et al. 2003). With the increased frequency of treatments provided by quotidian dialysis, the weekly phosphorus removal (261.2±124.2 mmol) by NHD was significantly higher than by SDHD (P=0.014) and CHD (P=0.03). The highly effective removal of phosphate with NHD not only allows the discontinuation of phosphate binders but in fact, in some patients phosphate has to be added to the dialysate in a concentration of 0.5-4.5 mg/dl in order to prevent the development of hypophosphatemia. In the London Daily/Nocturnal Hemodialysis Study, after being on NHD for a period of 10 months, 2 of the 11 patients needed phosphate supplementation in the dialysate to prevent the development of hypophosphatemia (Lindsay et al. 2003). Furthermore, patients on NHD experience negative calcium balance with increasing serum levels of parathyroid hormone and bone-specific alkaline phosphatase, 20 when a dialysate calcium concentration is 1.25 mmol/L. Hence, dialysate calcium concentration has to be increased to 1.75 mmol/L in NHD patients (Lindsay et al. 2003). Patients have likewise required phosphate supplementation in other studies of NHD (Lockridge et al. 2001).
In NHD patients requiring phosphate supplementation via the dialysate, as the blood passes through the dialyzer, phosphate is infused concurrently with calcium and bicarbonate since the concentrations of calcium and bicarbonate in the dialysate in NHD patients are 1.5-2.25 mmol/L and 28-35 mEq/L respectively. At the same time, inhibitors of calcification such as pyrophosphate (PPi) and citrate are dialyzed out. This chemical imbalance in the postdialyzer blood compartment, before it has equilibrated with rest of the blood compartment, is characterized by high calcium and phosphate levels in the presence of an alkaline pH, a microenvironment that is highly conducive to precipitation of calcium in the vessel wall. As this blood enters the heart and bathes the heart valves and the myocardium, there is an increased risk of calcification of the heart valves and the myocardium. The blood is then pumped by the heart into the major vessels and onto the smaller vessels thereby predisposing to calcification of the arterial tree.
A significant proportion of hemodialysis patients have subnormal serum levels of PPi. Serum PPi was below normal (<40 μg/dl) in about 40% of patients with normal serum alkaline phosphatase (n=42) and in about 60% of patients with elevated serum alkaline phosphatase (n=40) (David et al. 1973). Pyrophosphate deficiency may be a risk factor for deposition of calcium into the small vessels of the skin causing an inflammatory vasculitis called calciphylaxis that can lead to gangrene of the skin and underlying tissues, resulting in severe, chronic pain. Calciphylaxis may necessitate amputation of the affected limb and is commonly fatal. There is currently no effective treatment for this condition. Ectopic calcification, if left untreated, results in increased morbidity and death.
Thus, there exists a need for an effective method of maintaining adequate plasma concentrations of calcification inhibitors and inhibiting ectopic calcification in patients with kidney failure undergoing hemodialysis or peritoneal dialysis. The present invention, by administering to the dialysis patient a therapeutic amount of a pyrophosphate via the dialysate satisfies this need and provides related advantages as well.